1. Field of the Invention
The present invention relates to novel D-enantiomeric A-beta-oligomer-binding peptides derived from D3 and use thereof, particularly in medicine.
2. Discussion of Background Information
Due to the demographic development in the coming decades, the number of people suffering from age-related diseases will increase. Particularly noteworthy here is so-called Alzheimer's disease (AD, Alzheimer's dementia, latin=Morbus Alzheimer).
A feature of Alzheimer's disease are extracellular deposits of amyloid beta peptide (A-beta peptide). This deposition of A-beta peptide in plaques is typically determined post mortem in the brains of AD patients. Therefore, various forms of A-beta peptide—such as fibrils—are blamed for the emergence and progression of the disease. In addition, for some years the small, freely diffusible A-beta oligomers have been recognized as the major cause of the emergence and progress of AD.
A-beta monomers, as building blocks of A-beta oligomers, form continuously in the human body and are probably not toxic per se. They may even have a neuroprotective function. A-beta monomers can be randomly stored together depending on their concentration. The concentration is dependent on their rate of formation and rate of degradation in the body. An increase in the concentration of A-beta monomers occurs in the body with increasing age, such that spontaneous aggregation of the monomers to form A-beta oligomers is more likely. The A-beta oligomers thus formed could proliferate in analogy to prions and eventually lead to Alzheimer's disease.
No active ingredient or medicament currently exists that has an effect on the causes of AD. The medicaments currently used and approved alleviate some of the symptoms that occur in AD. However, they are not capable of slowing the disease progression or of bringing about a cure. Some substances exist which have shown success in animal experiments in the prevention, but not (necessarily) in the treatment, of AD.
An important difference between prevention and treatment or even cure of AD lies in the fact that prevention can potentially be achieved by preventing the formation of the first A-beta oligomers. A few A-beta ligands are adequate for prevention which do not necessarily have high affinity or selectivity with regard to A-beta oligomers.
The formation of A-beta oligomers from numerous monomers is a higher order reaction and is therefore dependent to a high degree on the A-beta monomer concentration. Therefore, a small reduction in the active A-beta monomer concentration already leads to prevention of the formation of the first A-beta oligomers. The preventive therapeutic concepts and substances currently in development are based on this mechanism.
In the treatment of AD, however, a completely new situation could be initiated. Here, A-beta oligomers or possibly also even larger polymers or fibrils are present which proliferate by prion-like mechanisms. However, this proliferation is a lower order reaction and is therefore scarcely dependent on the A-beta monomer concentration.
The substances known from the prior art reduce the concentration of A-beta monomers and/or oligomers in a variety of ways. For instance, gamma secretase modulators are known, which have been used for prevention in animal experiments.
Various sequences of D-amino acids which bind to A-beta peptides are known from WO 02/081505. These sequences of D-amino acids bind to amyloid beta peptides with a dissociation constant (KD) of 4 μmol.
Hybrid compounds, consisting of aminopyrazoles and peptides which prevent A-beta oligomerization, are known from WO 2011/147797.
For many substances which have shown positive results in animal experiments, this effect could not be confirmed in human clinical trials. In phase II and III clinical trials, only people who have been clearly diagnosed with AD are allowed to be treated. In this case, a small reduction in the A-beta monomer concentration is no longer adequate to prevent the formation of even more A-beta oligomers from those already present, e.g. by a prion-like mechanism. However, the proliferation of A-beta oligomers or even better their destruction or neutralization is absolutely necessary in order to influence the course of the disease.
Currently, AD is mainly diagnosed by neuropsychological tests by examining people in whom symptoms of dementia have already occurred. It is known, however, that A-beta oligomers and the fibrils and plaques formed therefrom over time in the course of the disease occur up to 20 years before the onset of symptoms in the brain of patients, and may have already caused irreversible damage. However, in practice there is currently no possibility of diagnosing AD before the outbreak of symptoms.
Thus, there still exists a requirement for novel compounds (active ingredients) which bind very specifically and with high affinity to A-beta oligomers, and thus prevent their proliferation. Said compounds should have no undesirable side effects and in particular not provoke any immune response. The compounds should also recognize toxic A-beta oligomers and therefore also the small, freely diffusible oligomers at low concentrations, and completely destroy and/or prevent the (prion-like) proliferation thereof.
Furthermore, there exists a need for novel compounds which can be used as probes for the detection and labeling of A-beta oligomers, in particular if the disease is not well advanced and the oligomers only occur at low concentrations.
A further object of the present invention was to provide substances which not only focus on extracellular A-beta peptides, like most compounds known from the prior art, but specifically bind soluble A-beta oligomers. Furthermore, the novel compounds should inhibit or prevent formation of fibrils of A-beta peptides.
It was also an object to provide novel peptides, preferably derivatives of the D-enantiomeric D-peptide D3 (SEQ ID NO: 11), which have efficient properties compared to D3. The properties include, inter alia, binding affinity and specificity for A-beta species, inhibition of A-beta fibril formation, inhibition of A-beta cytotoxicity, precipitation of A-beta oligomers and conversion of A-beta fibrils to non-toxic, non-amyloidogenic species.